The reversible acetylation of the c-amino groups of several lysine residues in the N-terminal histone tails mediates important conformational modifications in nucleosomes. These modifications influence the access of transcription factor to DNA and regulate gene expression (Davie, J. R. Curr. Opin. Genet. Dev. 1998, 8, 173-178). Two enzyme classes are involved in the process of acetylation and deacetylation of histones: histone acetyltransferases (HAT), which catalyse histone acetylation by acting as transcriptional co-activators, and histone deacetylases (HDAC).
After their recruitment to the promoter regions induced by transcription repressors and co-repressors such as Sin3, SMRT and N-CoR, histone deacetylases induce the formation of hypoacetylated histones and ultimately lead to transcriptional silencing (Wu, J. et al. Trends Biochem. Sci. 2000, 25, 619-623). The aberrant recruitment of histone deacetylases by oncogene proteins, or the disruption of the equilibrium between the activities of histone acetyltransferases and histone deacetylases are implicated in a series of pathologies, including:    1. Primarily, cancer (Lin, R. J. et al. Oncogene 2001, 20, 7204-7215; Kastner, P. et al. Oncogene 2001, 20, 7186-7203; Pandolfi, P. et al. Oncogene 2001, 20, 3116-3127; Grignani, F. et al. Nature 1998, 391, 815-818; Lutterbach, B. et al. Mol. Cell. Biol. 1998, 18, 7176-7184).    2. Non-tumor diseases:    Nervous system: Huntington's disease (Ferrante, R. J. et al. J. Neurosci. 2003, 23, 9418-9427; Hockey, E. et al. Proc. Natl. Acad. Sci. USA 2003, 100, 2041-2046);    diseases caused by triplet expansions (Bodai, L. et al. Curr. Med. Chem. 2003, 10, 2577-2587; Hughes, R. E. Curr. Biol. 2002, 12, R141-143);    neurodegenerative disorders (Jeong, M. R. et al. FEBS Lett. 2003, 542, 74-78);    ischemia (Ming, R. et al. J. Neurochem. 2004, 89, 1358-1367);    oxidative stress (Ryu, H. et al. Proc. Natl. Acad. Sci. USA 2003, 100, 4281-4286);    inflammatory responses of the nervous system (Suuronen, T. J. Neurochem. 2003, 87, 407-416);    epilepsy (Eyal, S. et al. Epilepsia 2004, 45, 737-744; Huang, Y. et al. J. Neurosci. 2002, 22, 8422-8428);    diseases caused by protein aggregates (Corcoran, L. J. et al. Curr. Biol. 2004, 14, 488-492);    Psychic diseases: bipolar disorders (Williams, R. S. B. et al. Nature 2002, 417, 292-295);    cognitive disorders (Levenson, J. M. US20060018921);    psychiatric disorders (Costa, E. et al. Crit. Rev. Neurobiol. 2003, 15, 121-142);    fragile X syndrome (Chandler, S. P. et al. BMC Mol. Biol. 2003, 4, 3; Chiurazzi, P. et al. Hum. Mol. Genet. 1999, 8, 2317-2323).    Infections: HIV (Adam, E. et al. Mol. Cell. Biol. 2003, 23, 6200-6209; Van Lint, C. et al. Embo J. 1996, 15, 1112-1120; Demonte, D. et al. Biochem. Pharmacol. 2004, 68, 1231-1238; Ylisastigui, L. et al. Aids 2004, 18, 1101-1108); malaria, leishmaniasis, infections by protozoa, fungi, phytotoxic agents, viruses and parasites.    Immune system: autoimmune diseases (Skov, S. et al. Blood 2003, 101, 1430-1438); chronic immune reactions against the host (Reddy, P. et al. Proc. Natl. Acad. Sci. USA 2004, 101, 3921-3926).    The heart: hypertrophy and cardiac decompensation (Kook, H. et al. J. Clin. Invest. 2003, 112, 863-871; McKinsey, T. A. et al. Novartis Found. Symp. 2004, 259, 132-141, discussion 141-145, 163-169; Hamamori, Y. et al. J. Clin. Invest. 2003, 112, 824-826).    Muscular system: fibrotic skin disease (Rombouts, K. et al. Exp. Cell. Res. 2002, 278, 184-197); fibrosis (Niki, T. et al. Hepatology 1999, 29, 858-867); spinal and bulbar muscular atrophy (Minamiyama, M. et al. Hum. Mol. Genet. 2004, 13, 1183-1192).    Others: arthritis (Chung, Y. L. et al. Mol. Ther. 2003, 8, 707-717); hyperlipidemia (Crestani, M. et al. WO05/105066); kidney diseases (Mishra, N. et al. J. Clin. Invest. 2003, 111, 539-552); psoriasis (McLaughlin, F. et al. Curr. Drug Targets Inflamm. Allergy 2004, 3, 213-219); intestinal and colitic diseases (Saemann, M. D. et al. Wien. Klin. Wochenschr. 2002, 114, 289-300); beta thalassemia (Rodgers, G. P. et al. Expert Opin. Investig. Drugs 2001, 10, 925-934); respiratory diseases (Barnes, P. J. Am. J. Respir. Crit. Care Med. 2003, 167, 813-818), Rubinstein-Taybi syndrome (Alarcon, J. M. et al. Neuron 2004, 42, 947-959).A number of histone deacetylase inhibitors are known, including natural products (e.g. trichostatin A (TSA), trapoxin (TPX), depsipeptide FK-228), short chain fatty acids (sodium-butyrate, -phenylbutyrate and -valproate) hydroxamates (e.g. suberoylanilide (SAHA), pyroxamide, scriptaid, oxamflatin, NVP-LAQ824) cyclic peptides containing hydroxamic acid (CHAPs) and benzamides (e.g. MS-275). All of them potently induce growth arrest, differentiation and apoptosis in a variety of transformed cells in culture as well in animal models (Marks, P. A. et al. Curr. Opin. Oncol. 2001, 13, 477-483). Several HDAC inhibitors such as, sodium phenylbutyrate (alone or in combination), depsipeptide, SAHA, pyroxamide, NVP-LAQ824 and MS-275 are being evaluated in clinical studies for the treatment of various tumor diseases (Johnstone, R. W Nat. Rev. Drug Discov. 2002, 1, 287-299). Their clinical benefit, however, is limited by toxicity problems (TSA, CHAPs, MS-275), low stability (TSA), low solubility (TSA), poor potency and lack of selectivity (butyrates and analogues) (Vigushin, D. et al. Anti-Cancer Drugs 2002, 13, 1-13).
To overcome these liabilities many derivatives have been synthesised based on the structures of the aforesaid compounds, with some molecular sub-structures hypothesised by certain authors as being useful for the activity and penetration of cellular structures (Miller, T. A. Expert Opin. Ther. Patents 2004, 14, 791-804; Miller, T. A. J. Med. Chem. 2003, 46, 5098-5116; Moradei, O. et al. Curr. Med. Chem.—Anticancer Agents 2005, 5, 529-560; Minucci, S. et al. Nature Reviews Cancer, 2006 6, 38-51).    WO 06/020004 describes HDAC inhibitors with the following general formula
where m, p1 and p2 are 0 or 1, R1 and R2 are, among other groups, C1-C10 alkyl, aryl, heteroaryl, C1-C10 alkylaryl or C1-C10 alkylheteroaryl.    WO 04/063169 describes histone deacetylase inhibitors of general formula
where R1 is an optionally substituted heterocycle which contains a nitrogen, R2 is hydroxylamine, R3 is, among other substituents, hydrogen, L1 is an optionally substituted —(CH2)n— group with n being between 0 and 6; L2 is an alkenyl chain.    WO 03/087066 describes HDAC inhibitors of general formula:
where A is phenyl or an optionally substituted heterocycle; m and n are from 0 to 4; and X can be the following group
where R1 and R2 are independently hydrogen or an optionally substituted C1-C4 alkyl chain.    WO 95/13264 describes N-hydroxypropenamides of general formula
where R1 is, among other groups, phenyl or aryloxyphenyl; L is a C1-C8 alkylene chain, —(CH2)m—O— (where m is a number from 0 to 4) or —CO—; n is 0 or 1; R2 is hydrogen, C1-C4 alkyl or arylalkyl; M is, among other groups, hydrogen. In J. Med. Chem. 2001, 44, 2069-2072, J. Med. Chem. 2002, 45, 1778-1784, J. Med. Chem. 2003, 46, 512-524, J. Med. Chem. 2003, 46, 4826-4829, J. Med. Chem. 2004, 47, 1098-1109, J. Med. Chem. 2004, 47, 1351-1359 and J. Med. Chem. 2005, 48, 3344-3353, Mai et al. describe a series of pyrrolyl hydroxyamides as selective histone deacetylase inhibitors.
HDAC inhibitors are also described in patent application PCT/EP2005/054949.
Several lines of research are currently ongoing in the field, focused both on the identification of new inhibitors having a broad-ranging action on all histone deacetylases, or inhibitors having a greater activity towards specific HDAC sub-classes.
In addition, based on the clinical and preclinical data of the first HDAC inhibitors and the great therapeutic potential of HDAC inhibition for various pathologies, the need for new inhibitors with improved pharmacological and chemico-physical properties is considerably high.
In particular, compounds endowed with increased inhibitory potency and metabolic stability could be extremely useful therapeutic agents with higher activity and longer duration of effect as compared to known inhibitors.